Solution- and Solid-State Conformations of C(α)-Alkyl Analogues of Methylphenidate (Ritalin) Salts: Avoidance of gauche⁺gauche^– Interactions

Abstract

Alkyl analogues of methylphenidate (Ritalin) salts are slow onset, long duration dopamine reuptake inhibitors with a potential use as a cocaine abuse pharmacotherapy. X-ray crystallographic studies and nuclear magnetic resonance (NMR) investigations strongly suggest that avoidance of sterically unfavorable gauche(-)gauche(+) orientations effectively influences both the C(α)-alkyl side chain conformation and the formation of a predominant rotamer about the CH-CH bond ligating piperidine and C(Ar)R moieties. The favored CH-CH rotamer in D(2)O and in CD(2)Cl(2) of the pharmacologically interesting i-Bu and CH(2)-cyc-Pnt (RS,RS)-salts has the same antiperiplanar arrangement that was found in the crystal structures, although there clearly is a fast equilibrium involving smaller amounts of synclinal partners. While the rotamer in the (RS,SR)-i-Bu HCl crystal structure exhibits a synclinal orientation for the vicinal pair of adjacent methine protons, the weighted time-averaged arrangement for these protons becomes almost completely antiperiplanar when the crystals are dissolved in D(2)O. Increased steric congestion around the CH-CH bond in the analogous N-methyl tertiary ammonium salts seems to augment the quantity of the preferred rotamer within the mixture. The stereochemistry of the species observed via NMR seems to arise from specific combinations of N-methyl orientation and avoidance of sterically unfavorable gauche(-)gauche(+) arrangements.

Conformational flexibility of xanthene‐based covalently linked dimers

“…Unless specified, all reagents and starting materials were purchased from commercial sources and used as received without purification. 1 H, 13 C, COSY, HSQC, and HMBC NMR spectra at room temperature were recorded using spectrometer operating at a field of 11.7 T (500 MHz for 1 H and 125 MHz for 13 C, Bruker-Spectrospin 500 Ultra Shield ™ ). Low-temperature NMR spectra were collected using two different spectrometers operating at a field of 17.6 T (700 MHz for 1 H and 175 MHz for 13 C, Varian vnmrs 700 Ytterbium) and 9.4 T (400 MHz for 1 H and 100 MHz for 13 C, Oxford NMR 400).…”

“…1 H, 13 C, COSY, HSQC, and HMBC NMR spectra at room temperature were recorded using spectrometer operating at a field of 11.7 T (500 MHz for 1 H and 125 MHz for 13 C, Bruker-Spectrospin 500 Ultra Shield ™ ). Low-temperature NMR spectra were collected using two different spectrometers operating at a field of 17.6 T (700 MHz for 1 H and 175 MHz for 13 C, Varian vnmrs 700 Ytterbium) and 9.4 T (400 MHz for 1 H and 100 MHz for 13 C, Oxford NMR 400). Spectra are described through chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons.…”

“…However, C2v conformer has high steric repulsion between protons 12 and 12′, so it is safe to conclude that (Xan + ) 2 is not locked in that structure. The dicationic molecule exhibits four degrees of freedom: (i, ii) the rotation of xanthylium moieties, defined by dihedral angles C 6 -C 7 -C 8 -C 13 and C 6′ -C 7′ -C 8′ -C 13′ , and (iii, iv) the rotation of the diphenyl ether moiety defined by dihedral angles C 12 -C 13 -O-C 13′ and C 12′ -C 13′ -O-C 13 (the numbering scheme is shown in Fig. 2A).…”

“…However, larger substituents on the diphenyl ether were shown to increase the barrier to 15 À 20 kcal/mol, [37] and similar behavior was observed in this work for (Xan-OH) 2 (vide infra). The information regarding the rotation of the Xan + moiety (defined by dihedral angles C 6 -C 7 -C 8 -C 13 and C 6′ -C 7′ -C 8′ -C 9′ ) cannot be extracted in a straightforward manner from the NMR spectra, because of the C2v symmetry of the xanthylium moiety. To evaluate the barriers for rotation of the Xan + moiety (defined by the C 6 -C 7 -C 8 -C 13 dihedral angle, labeled as α), DFT calculations were used to optimize the structure of the dication.…”

“…Besides their application in studies of electronic coupling between chromophores, CDs are also used as building blocks for molecular catalysis. Hindered rotation in covalently linked aryl dimers was extensively investigated using a range of 2D NMR techniques to obtain information about the rotamer structures, [7][8][9][10][11][12][13][14][15] while variable temperature NMR lineshape analysis was used to gain insight into rotamer interconversion kinetics. [16][17][18] These findings led to the development of chiral biaryl catalysts that were utilized in a number of asymmetric reactions, such as nitro-aldol condensations, [17] Michael additions, epoxidations, [17] and hetero Diels-Alder reactions.…”